Conditions that cause loss of bone mass and micro-architectural deterioration of bone structure affect many worldwide. For example, 44 million people age 50 or older are affected by osteoporosis in the United States alone. In addition, other conditions including, but not limited to, Paget's disease, osteolytic tumors, Rheumatoid Arthritis, Psoriatic Arthritis, Ankylosing Spondylitis, Osteoarthritis, osteopenia including drug induced osteopenia, and hypercalcemia also cause loss of bone mass and affect hundreds of millions of people worldwide.
These conditions predispose those suffering from these maladies to enhanced bone fragility and risk of fracture. Each condition has various etiologies such as congenital conditions, malnutrition, or various additional factors. For example, osteoporosis alone has at least three etiologies. The etiologies for osteoporosis have been established based on predisposing factors and clinical presentation, namely: postmenopausal (type I), senile (type II), and secondary (type III) osteoporosis. In all types, the declining ability of the bone remodeling machinery results in bone fragility. Type I postmenopausal osteoporosis (PMOP) occurs in women 51-75 years of age, in which, estrogen deficiency shifts bone remodeling to favor bone resorption over bone formation, which results in a net bone loss. Type II senile osteoporosis affects women at about twice the rate as men, and occurs from ages 75 to 90 years. Type III or secondary osteoporosis is caused by medications, cancers, endocrine disorders, chronic liver or kidney diseases, and additional conditions. The net result for each type of osteoporosis is the insidious loss of bone mass and the predisposition to traumatic bone fracture.
Numerous treatments have been administered to patients with these conditions; these treatments include the administration of hormone replacement therapy, antiresorptive agents, and immunosuppressants including monoclonal antibodies. However, administering therapeutic levels of these treatments often result in various side effects. For example, some treatments have been linked to various cancers, bone necrosis or osteonecrosis, and other unwanted side effects. Therefore, it is generally difficult to efficiently treat or prevent conditions that cause bone loss with the currently known compositions and methods.
Parathyroid hormone (PTH), also called parathormone or parathyrin, is a 84-residue peptide hormone secreted by chief cells of the parathyroid glands. It plays an important role on regulating extracellular calcium homeostasis, by acting upon the parathyroid hormone receptors (1 and 2) in bone, kidney, central nervous system, pancreas, testis and placenta. By binding to osteoblasts, PTH increases their expression of receptor activator of nuclear factor kappa-B ligand (RANKL) meanwhile decreases their expression of osteoprotegin (OPG), the latter is an inhibiter of interaction between RANKL and RANK. As a result, the binding of RANKL to RANK promotes bone resorption by forming new osteoclasts. hPTH (1-34) is a N-terminal fragment of PTH, and it is composed of 34 amino acid, expressing complete biological activity of PTH. However, according to the concentration in vivo, hPTH (1-34)/PTH can demonstrate exactly the opposite two bio-functions that high and sustained doses lead to bone resorption, but low doses lead to bone formation, therefore, hPTH (1-34)/PTH could be applied for treatment of bone-disease such as osteoporosis. However, similar to salmon calcitonin, the short half-life of hPTH (1-34)/PTH in vivo restricts its clinical application, although a therapeutic osteoporosis medicine, recombinant PTH (teriparatide, Forteo, Eli Lilly) has been approved by FDA almost 10 years ago
The insulin-like growth factors (IGFs) are proteins with high sequence similarity to insulin. The insulin-like growth factor-1, (IGF-1, also named somatomedin C), composed by 70 amino acids, has growth-promoting effects on cells including bone cells, which is being tested in clinical trials of osteoporosis, as one of approved agents by FDA. Similar to PTH, IGF-1 is also cleared rapidly through the kidney, but when bound to insulin-like growth factor binding protein-3 (IGFBP-3), the resultant recombinant complex evades renal clearance.